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Oncogene. 2018 May;37(21):2806-2816. doi: 10.1038/s41388-018-0163-x. Epub 2018 Mar 6.

Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner.

Author information

1
International Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111 - Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69007, Lyon, France.
2
Equipe labellisée "Ligue Nationale Contre le Cancer", Lyon, France.
3
Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
4
Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
5
Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
6
Collège de France - Paris Sorbonne, Inserm U944-CNRS 7212 - Université Paris Diderot, Lettre - 11 place Marcelin Berthelot, 75231, Paris Cedex 05, France.
7
International Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111 - Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69007, Lyon, France. chloe.journo@ens-lyon.fr.
8
Equipe labellisée "Ligue Nationale Contre le Cancer", Lyon, France. chloe.journo@ens-lyon.fr.
9
International Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111 - Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69007, Lyon, France. renaud.mahieux@ens-lyon.fr.
10
Equipe labellisée "Ligue Nationale Contre le Cancer", Lyon, France. renaud.mahieux@ens-lyon.fr.

Abstract

Since the identification of the antisense protein of HTLV-2 (APH-2) and the demonstration that APH-2 mRNA is expressed in vivo in most HTLV-2 carriers, much effort has been dedicated to the elucidation of similarities and/or differences between APH-2 and HBZ, the antisense protein of HTLV-1. Similar to HBZ, APH-2 negatively regulates HTLV-2 transcription. However, it does not promote cell proliferation. In contrast to HBZ, APH-2 half-life is very short. Here, we show that APH-2 is addressed to PML nuclear bodies in T-cells, as well as in different cell types. Covalent SUMOylation of APH-2 is readily detected, indicating that APH-2 might be addressed to the PML nuclear bodies in a SUMO-dependent manner. We further show that silencing of PML increases expression of APH-2, while expression of HBZ is unaffected. On the other hand, SUMO-1 overexpression leads to a specific loss of APH-2 expression that is restored upon proteasome inhibition. Furthermore, the carboxy-terminal LAGLL motif of APH-2 is responsible for both the targeting of the protein to PML nuclear bodies and its short half-life. Taken together, these observations indicate that natural APH-2 targeting to PML nuclear bodies induces proteasomal degradation of the viral protein in a SUMO-dependent manner. Hence, this study deciphers the molecular and cellular bases of APH-2 short half-life in comparison to HBZ and highlights key differences in the post-translational mechanisms that control the expression of both proteins.

PMID:
29507418
DOI:
10.1038/s41388-018-0163-x
[Indexed for MEDLINE]

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